Colon cancer happens following a series of transitions, from a normal colorectal crypt to an adenoma that ends up in a carcinoma and eventually in metastasis localized normally in the liver. These events are ruled by a group of genetic and molecular alterations (familiar syndromes HNPCC, FAP and sporadic cancers CIN-LOH and MSI) that is translated by the activation of proto-oncogenes or by the lost of tumor or metastasis suppressor genes. TGF-β receptors and their associated signal transduction pathways have been particularly studied and incriminated in the late stages of human colon carcinogenesis, having a pejorative role. But interestingly, information concerning the incrimination of BMPs in this context is rare. When my PhD project stated, an article exposed an anti-inflammatory role for BMP-7 in rat's gut, suggesting that this cytokine could have a direct and beneficial role on colon epithelial and stoma cells. The BMPs act upon several type II receptors (BMPRII, ActR-II, ActR-IIB), type I receptors (ALK-2, ALK-3, ALK-6) and upon SMAD proteins (SMAD1, SMAD4, SMAD5, SMAD8). However, 50% of metastatic colon cancers present one or more mutations on SMAD4. Also, germinal mutations on ALK-3 gene happen in 38% of patients with juvenile polyposis. Never the less, 83% of the studied MSI colon tumors have a mutation on the ActR-II gene. In this context, my PhD project was centered in the expression and role of BMP-7 in human colon cancer progression. We have demonstrated by RT-PCR, immunohistochemistry and ELISA that BMP-7 and its receptors are present in histologically normal human crypts, in aberrant crypt foci in sigmoiditis, in human colorectal tumors and in several colorectal cancer cell lines. We have also demonstrated that BMP-7 is a scatter and invasion factor. This invasive capacity of BMP-7 is independent of SMAD4 and src activity, but is associated to the cyclic activation of RhoGTPases (Rac1 and RhoA), to FAK activation (tyr925 phosphorylation associated with angiogenesis and invasion) and to MAPK/SAPK activation (JNK and ERK1/2). Taken together my PhD work strongly suggests that BMP-7 acts as dissemination and a proinvasive factor via an autocrine and paracrine mechanism. This cytokine has divergent roles on human colon cancer progression. A beneficial role, by opposing itself to inflammation and a pejorative role by helping cancer progression on the latest stages associated to invasive capacity and to adenoma-carcinoma transition. In parallel, we have demonstrated that the α1 integrine takes part in the molecular scaffold implicated in the src-stimulated cellular invasion. Also we have shown that VEGF is a cellular invasion inductor in colorectal cancer epithelial cells, and that the tumor cells-secreted VEGF acts upon endothelial cells in order to induce angiogenesis and to ensure growth and survival of the tumor.
